Neoadjuvant Chemoradiation Therapy Group Research Articles

A Surrogate Endpoint for Overall Survival in Locally Advanced and Resectable Esophageal Squamous Cell Carcinoma: A Reanalysis of Data From the NEOCRTEC5010 Trial

This study aimed to investigate disease-free survival (DFS) as a surrogate endpoint for overall survival (OS) in patients with locally advanced and resectable esophageal squamous cell carcinoma. We re-analyzed patient data from the NEOCRTEC5010 randomized controlled trial (N=451 patients) to compare their OS with that of an age- and sex-matched cohort from the general population of China. We used expected survival and the standardized mortality ratio, respectively, in our analysis of data collected from a neoadjuvant chemoradiation therapy (NCRT) plus surgery group and a surgery-only group. Published data from 6 randomized controlled trials and 20 retrospective studies were used to examine the correlation between DFS and OS at the trial level. The annual hazard rate of disease progression decreased to 4.9% and 8.1% within 3 years in the NCRT and surgery groups, respectively. Patients who were disease-free at 36 months had a 5-year OS of 93.9% (95% CI, 89.7%-98.4%) in the NCRT group with a standardized mortality ratio of 1.1 (95% CI, 0.7-1.8; P=.5639). In contrast, the 5-year OS was only 12.9% (95% CI, 7.3%-22.6%) for patients in the NCRT group who exhibited disease progression within 36 months. At the trial level, DFS and OS were correlated with treatment effect (R2=0.605). Disease-free status at 36 months is a valid surrogate endpoint for 5-year OS in patients with locally advanced and resectable esophageal squamous cell carcinoma. Patients who were disease-free at 36 months showed a favorable OS, which was indistinguishable from that of the age- and sex-matched comparison group from the general population; otherwise, their 5-year OS was extremely poor.

Pathologic Response to Neoadjuvant Sequential Chemoradiation Therapy in Locally Advanced Breast Cancer: Preliminary, Translational Results from the French Neo-APBI-01 Trial

Radiation therapy (RT), a novel approach to boost the anticancer immune response, has been progressively evaluated in the neoadjuvant setting in breast cancer (BC). We aimed to evaluate immunity-related indicators of response to neoadjuvant chemoradiation therapy (NACRT) in BC for better treatment personalization. We analyzed data of the first 42 patients included in the randomized phase 2 Neo-APBI-01 trial comparing standard neoadjuvant chemotherapy (NACT) and NACRT regimen in locally advanced triple-negative (TN) and luminal B (LB) subtype BC. Clinicopathological parameters, blood counts and the derived parameters, total tumor-infiltrating lymphocytes (TILs) and their subpopulation, as well as TP53 mutation status, were assessed as predictors of response. Twenty-one patients were equally assigned to each group. The pathologic complete response (pCR) was 33% and 38% in the NACT and NACRT groups, respectively, with a dose-response effect. Only one LB tumor reached pCR after NACRT. Numerous parameters associated with response were identified, which differed according to the assigned treatment. In the NACRT group, baseline hemoglobin of ≥13 g/dL and body mass index of <26 were strongly associated with pCR. Higher baseline neutrophils-to-lymphocytes ratio, total TILs, and T-effector cell counts were favorable for pCR. This preliminary analysis identified LB and low-TIL tumors as poor responders to the NACRT protocol, which delivered RT after several cycles of chemotherapy. These findings will allow for amending the selection of patients for the trial and help better design future trials of NACRT in BC.

The immunological impact of preoperative chemoradiotherapy on the tumor microenvironment of pancreatic cancer.

Several therapeutic regimens, including neoadjuvant chemoradiation therapy (NACRT), have been reported to serve as anticancer immune effectors. However, there remain insufficient data regarding the immune response after NACRT in pancreatic ductal adenocarcinoma (PDAC) patients. Data from 40 PDAC patients that underwent surgical resection after NACRT (NACRT group) and 30 PDAC patients that underwent upfront surgery (US group) were analyzed to examine alterations in immune cell counts/distribution using a multiplexed fluorescent immunohistochemistry system. All immune cells were more abundant in the cancer stroma than in the cancer cell nest regardless of preoperative therapy. Although the stromal counts of CD4+ T cells, CD20+ B cells, and Foxp3+ T cells in the NACRT group were drastically decreased in comparison with those of the US group, counts of these cell types in the cancer cell nest were not significantly different between the two groups. In contrast, CD204+ macrophage counts in the cancer stroma were similar between the NACRT and US groups, while those in the cancer cell nests were significantly reduced in the NACRT group. Following multivariate analysis, only a high CD204+ macrophage count in the cancer cell nest remained an independent predictor of shorter relapse‐free survival (odds ratio = 2.37; P = .033). NACRT for PDAC decreased overall immune cell counts, but these changes were heterogeneous within the cancer cell nests and cancer stroma. The CD204+ macrophage count in the cancer cell nest is an independent predictor of early disease recurrence in PDAC patients after NACRT.

Choline metabolism is associated with pathological response and recurrence of patients with pancreatic cancer after neoadjuvant chemoradiation therapy

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis even if it is resectable. Although the efficacy of neoadjuvant therapies for PDAC are reported in recent years, it is still unclear the optimal target of neoadjuvant therapy. We investigated the metabolic changes in PDAC to identify mechanisms of treatment effect of neoadjuvant chemoradiation therapy (NACRT). Methods: Frozen tissue of tumor and normal pancreas were obtained from 49 patients with PDAC who underwent surgery. There were 30 patients who received NACRT (NACRT group) and 19 patients who did not receive any neoadjuvant therapy (control group). Metabolites levels of tumor and normal pancreatic tissue were measured by capillary electrophoresis-mass spectrometry (CE-MS). In NACRT group, pathological responses were classified according to Evans grade (evans grade Ⅰ～ⅡA; resistant group (n=19), ⅡB～Ⅳ; response group (n=10) ). RNA microarray was also performed for NACRT group (10 patients) and control group (5 patients). Results: In comparison of metabolite levels of tumor, there were significant differences in 22 metabolites between NACRT group and control group. There were significant differences in 9 metabolites between response group and resistant group. Among these 9 metabolites, only phosphocholine was associated with recurrence in NACRT group. RNA microarray showed marked gene suppression of choline transporter in PDAC tissue of NACRT group. Conclusion: Present study, identify new metabolic consequences of PDAC and potential target of NACRT. Choline metabolism is associated with pathological responses and prognosis in patients with PDAC who received NACRT.

The prognostic impact of neoadjuvant chemoradiotherapy on lymph node sampling in patients with locally advanced rectal cancer

According to the American Joint Committee on Cancer, at least 12 lymph nodes are required to accurately stage locally advanced rectal cancer (LARC). Neoadjuvant chemoradiation therapy (NACRT) reduces the number of lymph nodes retrieved during surgery. In this study, we evaluated the effect of NACRT on lymph node retrieval and prognosis in patients with LARC. We performed an observational study of 142 patients with LARC. Although our analysis was retrospective, data were collected prospectively. Half the patients were treated with NACRT and total mesorectal excision (TME) and the other half underwent TME only. The number of lymph nodes retrieved and the number of metastatic lymph nodes were significantly reduced in the NACRT group (P > 0.001). In the univariate and multivariate analyses, only NACRT and patient age were significantly associated with reduced lymph node retrieval. The number of metastatic lymph nodes and the lymph node ratio (LNR) both had a significant effect on prognosis when the patient population was examined as a whole (P = 0.003 and P = 0.001, respectively). However, the LNR was the only significant, independent prognostic factor in both treatment groups (P = 0.007 for the NACRT group; P = 0.04 for the no-NACRT group). NACRT improves patient prognosis only when the number of metastatic lymph nodes is reduced. The number of metastatic lymph nodes and the LNR are important prognostic factors. Lymph node retrieval remains an indispensable tool for staging and prognostic assessment of patients with rectal carcinoma treated with NACRT.

Preoperative MDCT Assessment of Resectability in Borderline Resectable Pancreatic Cancer: Effect of Neoadjuvant Chemoradiation Therapy.

The purpose of this study is to evaluate the diagnostic performance of MDCT in assessing tumor resectability in patients with borderline resectable pancreatic cancers after receiving neoadjuvant chemoradiation therapy (CRT) in comparison with those undergoing upfront surgery. Thirty-seven patients with borderline resectable pancreatic cancers were randomly allocated to the neoadjuvant CRT group (arm 1; n = 18) or up-front surgery group (arm 2; n = 19). Three radiologists rated the likelihood of local resectability on a 5-point scale at preoperative MDCT in two separate sessions (session 1: post-CRT of arm 1, baseline of arm 2; session 2: using new imaging criteria reflecting the changes during CRT of arm 1). The AUC of each reviewer, as well as sensitivity, specificity, and accuracy based on consensus interpretation, were compared between arms and sessions. For local resectability (n = 30), AUC values at session 1 were 0.664, 0.669, and 0.588 for reviewers 1, 2, and 3, respectively, and were not significantly different between arms 1 (n = 15; 0.759, 0.713, and 0.593) and 2 (n = 15; 0.852, 0.685, and 0.722) (p > 0.05). In arm 1, MDCT sensitivity, specificity, accuracy were 22%, 100%, and 53%, respectively, at session 1 versus 78%, 67%, and 73%, respectively, at session 2 (p > 0.05). In patients with borderline resectable pancreatic cancers, neoadjuvant CRT did not significantly decrease the performance of MDCT for the prediction of local resectability. However, by considering post-CRT changes, such as nonprogression in tumor-vascular contact, MDCT may provide better sensitivity for locally resectable disease.

Neoadjuvant Radiation Therapy in Locally Advanced Colon Cancer: a Cohort Analysis

BackgroundA paucity of data exists in the use of neoadjuvant chemoradiation therapy (NRT) for T4, non-metastatic colon cancer. This study was conducted to determine the effect of NRT on outcomes after resection for T4 colon cancer. MethodsAll patients with non-metastatic resected clinical T4 colon cancer from 2000 to 2012 at a tertiary care center were included. The cohort was divided into two groups—those that received NRT and those that did not (non-NRT). The primary outcomes were margin-negative resection and overall survival (OS). ResultsOne hundred and thirty-one consecutive patients with non-metastatic clinical T4 colon cancer with a mean age of 65 years were included. NRT was used in 23 patients (17.4%). NRT group was noted to have non-statistically significant improvement in R0 resection rate (NRT 95.7% vs non-NRT 88.0%; p = 0.27) and local recurrence (NRT 4.3% vs non-NRT 15.7%; p = 0.15). There was a significant difference in T-stage downstaging between the two groups (NRT 30.4% vs non-NRT 6.5%; p = 0.007). In a bivariate analysis, NRT was associated with improved 5-year OS (NRT 76.4% vs non-NRT 51.5%; p = 0.03). This relationship did not persist in a Cox proportional hazard analysis that included age and comorbidity (HR 2.19; 95% CI 0.87–5.52; p = 0.09). ConclusionsThe use of NRT in locally advanced T4 colon cancer is safe and associated with increased downstaging. While there was a trend toward improvement in local recurrence and the ability to obtain margin-negative resections in the NRT group, this was not significant. Significantly improved overall survival was not observed in a multivariable analysis.

Is Higher Dose Radiation Beneficial As Part of a Neoadjuvant Chemoradiation Therapy Protocol for Resectable Esophageal Cancer? A Meta-analysis

Neoadjuvant chemoradiation therapy (NCRT) for resectable esophageal carcinoma has improved survival rates in patients with locally advanced disease. However, the appropriate neo-adjuvant radiation dose is debated. This meta-analysis aims to evaluate if as part of a NCRT protocol, radiation dose affects survival in patients with locally advanced esophageal cancer. A comprehensive search of MEDLINE, EMBASE, PubMed, SCOPUS and the Cochrane database was conducted (1996-present). All randomized control trials of patients with esophageal carcinoma undergoing NCRT compared to surgery alone were included; study quality was assessed using CONSORT checklist. Pooled risk ratio along with the 95% confidence interval (CI) for overall survival (OS) and progression-free survival (PFS) at 1, 3 and 5 years were calculated. Search strategy yielded 111 studies, of which 10 studies met the selection criteria with a total of 1628 patients: 813 received NCRT, and 815 had surgery upfront. Meta-analysis of included data showed an increased OS at 1, 3, and 5-years (RR=1.10, 95% CI:0.99 – 1.22, p=0.09; RR=1.29, 95% CI:0.98 – 1.70, p = 0.07; RR= 1.39, 95% CI: 1.16 – 1.85, p <0.01, respectively); and PFS at 1, 3, and 5-years (RR=1.16, 95% CI 0.91 – 1.49, p=0.24; RR=1.37, 95% CI:1.14 – 1.65; p <0.01; RR=1.57, 95% CI:1.24 – 1.99; p <0.01, respectively) for NCRT group. For patients treated with NCRT, 584 were treated with less than 45 Gy, and 229 were treated with 45 Gy or more. Subgroup analysis showed significantly improved survival at 3, and 5-years (RR=1.38, 95%CI: 1.11 – 1.72, p<0.01; RR=1.40, 95% CI: 1.14–1.72; p<0.01, respectively) with patients treated at less than 45 Gy. Neoadjuvant chemoradiation therapy improves OS at 5 years in locally advanced esophageal cancer. This effect is especially pronounced in patients treated with less than 45 Gy as part of NCRT. Further prospective study of appropriate radiation dose for NCRT is warranted.

Pancreatic intraepithelial neoplasia and histological changes in non‐neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma

To study the histological changes in non-neoplastic pancreas and the effects on pancreatic intraepithelial neoplasia (PanIN) after neoadjuvant chemoradiation therapy (NCRT) for pancreatic ductal adenocarcinoma (PDAC). We reviewed the archival H&E slides from 218 patients with PDAC who completed NCRT and pancreaticoduodenectomy. Sixty-five patients who underwent pancreaticoduodenectomy for PDAC without NCRT were used as controls. Various histological features were reviewed and correlated with NCRT and survival. The NCRT group had lower densities of PanIN2 (P = 0.004) and PanIN3 (P = 0.02) than the control group. The extent of fibrosis, the frequency of neuroma-like nerve proliferation and the frequency of islet cell aggregation were significantly higher in the NCRT group than in the control group (P < 0.05). The intensity of inflammation was less in the NCRT group than in the control group (P = 0.02). In the NCRT group, patents with moderate to severe fibrosis or grade 2 inflammation had poorer survival than those with mild fibrosis (P = 0.04) or those with grade 0 or grade 1 inflammation (P = 0.003), respectively. Non-neoplastic pancreatic tissue from patients who received NCRT had a reduced density of high-grade PanIN lesions, more pancreatic fibrosis, and higher frequencies of neuroma-like nerve proliferation and islet cell aggregation, but less inflammation, compared to tissue from those who did not receive NCRT.

Novel aspects of preoperative chemoradiation therapy improving anti‐tumor immunity in pancreatic cancer

Pancreatic cancer is an aggressive cancer with poor prognosis. Little is known about the immune response in the tumor microenvironment after chemotherapy for initially unresectable tumor. The purpose of this study was to investigate the immunological effects of chemoradiation therapy in the tumor microenvironment of pancreatic adenocarcinoma. Seventeen patients with pancreatic adenocarcinoma with and without preoperative chemoradiation therapy were retrospectively analyzed using immunohistochemical methods for HLA class I heavy chain, CD4(+), CD8(+), CD45RO(+) and Foxp3(+) T cell infiltrations. Seven of the 17 study patients received preoperative chemoradiation therapy. There were no statistically significant differences in the number of CD4(+) and CD8(+) T cell infiltrations in the tumor microenvironment. However, the number of Foxp3(+) T cell infiltrations was significantly lower in the neoadjuvant chemoradiation therapy group. The HLA class I expression status was the same between the two groups. In conclusion, preoperative chemoradiation therapy in pancreatic adenocarcinoma is useful for reducing regulatory T cell levels in combination with its direct cytotoxic effects.

Robotic-assisted Ivor Lewis esophagectomy with or without neoadjuvant chemoradiation therapy for esophageal cancer.

117 Background: Neoadjuvant chemoradiation therapy (NT) has become standard of care for patients with locally advanced esophageal cancer. In selected patients, robotic-assisted Ivor Lewis esophagectomy (RAIL) is a safe and feasible operative strategy in the management of esophageal cancer. This study was designed to determine potential differences in peri-operative morbidity and short term outcomes in patients with esophageal cancer treated with RAIL with or without NT. Methods: A retrospective review of consecutive patients with esophageal cancer who underwent RAIL esophagectomy between October 2010 and June 2012 with and without NT was performed. Clinical and pathological variables were analyzed with two-sided student t-test assuming equal variance. Data were considered significant at a p-value &lt;0.05. Results: Eighty-nine patients underwent RAIL during the study period. Seventy-seven patients (87%) received NT and twenty-two patients did not (13%). The median age was 66 years (range 44 – 84) and the median BMI was 28 kg/m2(range 16.7 – 40.1). All patients had a R0 resection. There were no differences in the mean estimated blood loss (149 vs.153 mL; p = 0.52) and mean operative times (434 vs. 427 minutes; p = 1.0). There were no differences in the incidence of pneumonia or atrial fibrillation, lengths of stay in the ICU, or length of hospitalization. In total, there were two anastomotic leaks and one leak from the gastric conduit. The anastomotic leaks occurred in the group that did not receive NT and the gastric conduit leak occurred in the group that received NT. There were no mortalities in either group. There was no difference in the mean number of lymph nodes harvested in the NT group (22 ± 11 vs. 20 ± 8, p = 0.41). Conclusions: RAIL can be safely performed following neoadjuvant chemoradiation therapy.In this series there were similar perioperative, morbidity and short-term mortality outcomes in patients who received NT compared with RAIL alone. Longer follow-up is required in order to determine long term oncologic outcome.

Neo-adjuvant Chemoradiation Therapy Using S-1 Followed by Surgical Resection in Patients with Pancreatic Cancer

ObjectiveThe aim of this study was to compare short-term surgical results in pancreatic cancer patients who underwent surgical resection after neo-adjuvant chemoradiation therapy (NACRT) using S-1. MethodsThe study population comprised 77 patients with pancreatic cancer between 2006 and 2010. Out of 34 patients who underwent staging laparoscopy between 2008 and 2010, 31 patients without occult distant organ metastasis underwent chemoradiation and of whom 30 underwent pancreatectomy (NACRT group). Of the other 43 patients, 36 underwent surgical resection in 2006–2008, followed by adjuvant therapy (adjuvant group). The primary endpoint was frequency of pathological curative resection (R0). ResultsThe new regimen of NACRT was feasible and safe. Twenty-eight of 30 (93%) patients in the NACRT group had R0 resection, which was significantly higher than in the adjuvant group (21 of 36 patients, 58%, p = 0.005). The number and extent of metastatic lymph nodes in the NACRT group (1 (0–25), N0/1; 18 of 38) was significantly lower than in the adjuvant group (2 (0–19), N0/1; 23 of 30), p = 0.0363). The frequency of intractable ascites in the NACRT group (eight of 30) was significantly higher than in the adjuvant group (two of 36, p = 0.035). ConclusionNeo-adjuvant chemoradiation therapy using S-1 followed by pancreatectomy can improve the rate of pathologically curative resection and reduces the number and extent of lymph node metastasis.

Surgical Results After Preoperative Chemoradiation Therapy for Patients With Pancreatic Cancer

The results of surgical therapy alone for pancreatic cancer are disappointing. We explored surgical results after neoadjuvant chemoradiation therapy (NACRT) for patients with pancreatic cancer that extended beyond the pancreas. Sixty-eight consecutive patients with pancreatic cancer who underwent pancreatic resection were included. Twenty-seven patients underwent surgical resection after NACRT (NACRT group). The other 41 patients were classified as surgery-alone group. Surgical results were compared in patients who underwent curative resection (R0/1) who were followed up for at least 25 months and underwent no adjuvant therapy. A lower frequency of lymph node metastasis was observed in the NACRT group (P < 0.05). The frequency of residual tumor grading in the NACRT group was significantly different from that in surgery-alone (R0/1/2%, 52/15/33 vs 22/51/27; P = 0.0040). In R0/1 cases, overall survival and disease-free survival rates in the NACRT group (n = 18) were significantly longer than in surgery-alone (n = 30, P < 0.05). The rate of local recurrence in the NACRT group was significantly less than in surgery-alone (11% vs 47%, P = 0.0024). This single-institution experience indicates that NACRT is able to increase the resectability rate with clear margins and to decrease the rate of metastatic lymph nodes, resulting in improved prognosis of curative cases with pancreatic cancer that extended beyond the pancreas.